ferroptosis

Overview

Ferroptosis is a form of regulated cell death characterized by the accumulation of lipid peroxides to lethal levels, which is distinct from other forms of cell death such as apoptosis and necroptosis. This iron-dependent process is driven by oxidative stress and is implicated in various physiological and pathological conditions, including cancer, neurodegeneration, and organ damage. The mechanism of ferroptosis involves the depletion of glutathione (GSH), a critical antioxidant, and the inactivation of glutathione peroxidase 4 (GPX4), leading to increased reactive oxygen species (ROS) and subsequent lipid peroxidation. Given its role in tumor suppression and disease progression, ferroptosis has emerged as a promising therapeutic target in cancer treatment and other diseases.

Focus of Latest Publications

Recent research demonstrates ferroptosis as a promising therapeutic target across multiple cancer types and disease states. In oncology, ferroptosis induction has been evaluated in triple-negative breast cancer using the repurposed antiparasitic nitazoxanide, in hepatocellular carcinoma through exosome-like nanovesicles and natural compounds like noni juice, and in gastric, bladder, and pancreatic cancers via multiple pharmacological and nanomaterial-based approaches. Notably, pulmonary sarcomatoid carcinoma exhibits an elevated ferroptosis suppression signature, suggesting vulnerability to ferroptosis-inducing strategies targeting iron transporters and glutathione metabolism. These studies collectively identify ferroptosis induction as a mechanism to overcome therapeutic resistance in malignancies ranging from lung carcinomas to osteosarcomas.

The molecular basis of ferroptosis-based therapeutics consistently involves disruption of iron homeostasis and the antioxidant defense system. Multiple studies document that effective ferroptosis induction occurs through downregulation of GPX4 and SLC7A11, depletion of glutathione, accumulation of intracellular iron, elevated reactive oxygen species, and lipid peroxidation with associated mitochondrial damage. The Nrf2/HO-1-GPX4 and Nrf2/SLC7A11 signaling axes emerge as central regulatory nodes, with diverse therapeutic agents—ranging from natural polyphenols and traditional medicine formulations to engineered nanoparticles—converging on these pathways to initiate ferroptotic cell death.

A critical emerging insight is the synergy between ferroptosis and anti-tumor immunity. GALNT7-dependent ferroptosis suppression was identified as a mechanism of immunotherapy resistance in non-small cell lung cancer, and its silencing enhanced CD8+ T cell infiltration and interferon-gamma production while sensitizing tumors to anti-PD-1 therapy. Ferroptosis operates as an immunogenic cell death modality distinct from apoptosis, generating danger signals that activate dendritic cells and T-lymphocytes, thereby converting "cold" immune-excluded tumors into responsive states amenable to checkpoint inhibition and establishing immunological memory.

Beyond oncology, ferroptosis modulation addresses neurodegenerative and inflammatory pathologies. In Parkinson's disease, ferroptosis represents a key driver of dopaminergic neuronal degeneration, and targeted iron-chelating and antioxidant nanotherapeutics restored neuronal viability and motor function in models. In Alzheimer's disease, impaired mitophagy disrupts redox and iron homeostasis, increasing neuronal susceptibility to ferroptosis in a self-amplifying cycle. Additional therapeutic applications include attenuation of hepatic fibrosis through microbiota-dependent ferroptosis inhibition, amelioration of radiation enteritis via engineered probiotics, and reduction of myocardial injury in obesity-related cardiomyopathy through ferroptosis suppression.

Therapeutic delivery platforms have diversified to include natural product derivatives, exosome-based carriers, metal-organic framework nanocomposites with calcium overload capacity, photodynamic-ferroptotic hybrid nanomaterials, and genetically engineered probiotic systems. These strategies leverage the elevated oxidative stress microenvironment of target pathological cells—whether senescent, cancerous, or inflammatory—to achieve selective ferroptosis induction while sparing healthy tissues, thereby improving therapeutic safety and efficacy.

Key Publications

• NEWJun Repurposing nitazoxanide as a novel ferroptosis inducer for triple-negative breast cancer via dual disruption of iron homeostasis and the β-catenin/GPX4 axis. (Redox report : communications in free radical research, 2026, PMID 42371677): "Ferroptosis induction is a promising triple-negative breast cancer (TNBC) therapy, but current inducers are suboptimal."
• NEWJun Multi-omics profiling unveils biological and clinical insights into pulmonary sarcomatoid carcinoma. (Cell reports. Medicine, 2026, PMID 42361801): "We find an elevated ferroptosis suppression signature in PSC tumors and demonstrate their vulnerability to ferroptosis by targeting FTL and SLC3A2."
• NEWJun Integrating Machine Learning and Single-Cell Analysis to Reveal the Diagnostic and Therapeutic Value of Regulated Cell Death Mechanisms in Hepatocellular Carcinoma. (FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026, PMID 42338358): "Regulated cell death (RCD) pathways play a pivotal role in the development and progression of various cancers, offering potential prognostic indicators and biomarkers of drug sensitivity for HCC patients."
• NEWJun Single-Cell Reveal GALNT7-Dependent Ferroptosis Suppression as a Mechanism of Immunotherapy Resistance in Non-Small Cell Lung Cancer. (Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026, PMID 42318657): "Functional and pathway analyses linked GALNT7 expression to suppression of ferroptosis-related signaling, whereas ICB responders (R) exhibited higher ferroptosis activity."
• May DIA-based proteomic analysis reveals Scutellaria barbata D. Don Exosome-like nanovesicles promote ferroptosis in HCC through Nrf2/SLC7A11/GPX4 pathway. (Functional & integrative genomics, 2026, PMID 42209785): "SBENs induced HepG2 ferroptosis via mitochondrial dysfunction and Nrf2/SLC7A11/GPX4 pathway inhibition, effectively triggering HCC ferroptosis in subcutaneous tumor xenografts with safety profiles."
• Jun Reactive Oxygen Species-Responsive Targeted Polydopamine-Rosmarinic Acid Nanotherapeutics for Ferroptosis-Driven Parkinson's Disease Modulation in Caenorhabditis elegans. (ACS applied bio materials, 2026, PMID 42159234): "In particular, ferroptosis, an iron cell death mechanism, is a key driver of PD pathogenesis, and its modulation represents a feasible therapeutic target."
• May Noni (Morinda citrifolia L.) fruit juice induces ferroptosis in gastric cancer cells via the Nrf2/HO-1-GPX4 axis. (Food & function, 2026, PMID 42132559): "This study investigates the mechanism by which noni juice targets ferroptosis in gastric cancer (GC) and analyzes its bioactive components."
• May Single-nucleus RNA sequencing reveals ferroptosis as a potential contributor to the pathogenesis of focal cortical dysplasia. (Clinical and translational medicine, 2026, PMID 42051157): "This study aimed to characterize the cellular heterogeneity of FCD and investigate the function of ferroptosis in FCD pathogenesis."
• May NK92-exo Induces Ferroptosis in A549 Cells by Targeting a miR-663a-SLC11A2 Axis. (Anticancer research, 2026, PMID 42049360): "This study investigates whether exosomes derived from NK-92 cells (NK92-exo) can trigger ferroptosis in A549 cells and elucidates the underlying mechanisms, providing a novel strategy for lung cancer treatment."
• Jun Blood-based biomarkers of ferroptosis in Parkinson's disease. (Neurobiology of disease, 2026, PMID 42035924): "This study aimed to identify blood biomarkers of ferroptosis for predicting the progression of Parkinson's disease at the stage of L-DOPA-related complications."